Preparation of camptothecin and of its derivatives

ABSTRACT

The present invention relates to a novel process for preparation of camptothecin and of its derivatives by convergent synthesis starting from a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid and to the intermediates obtained.

[0001] The present invention relates to the preparation of camptothecin and of its derivatives. It relates more particularly to the preparation of camptothecin, of topotecan and of irinotecan.

[0002] Camptothecin derivatives of general formula:

[0003] in which in particular R₁ is hydrogen, halogen or alkyl and X is a chlorine atom or NR₂R₃ for which R₂ and R₃, which are identical or different, can represent a hydrogen atom, an optionally substituted alkyl radical, an optionally substituted carbocyclyl, an optionally substituted heterocycle or alkyl radicals (optionally substituted) which form, with the nitrogen atom to which they are attached, a heterocycle optionally comprising another heteroatom chosen from O, S and/or NR₄, R₄ being a hydrogen atom or an alkyl radical, and in which the X—CO—O— group is situated at the 9-, 10- or 11-position of the A ring are known according to European Patent EP 137 145, cited here by way of reference. These camptothecin derivatives are anticancer agents which are topoisomerase I inhibitors, among which irinotecan, for which X—CO—O— is [4-(1-piperidino)-1-piperidino]carbonyloxy, is an active principle which is particularly effective with respect to solid tumours and in particular colorectal cancer.

[0004] Other camptothecin derivatives which are mentioned as anticancer agents, in particular derivatives with a structure analogous to the structure given above, in which structure X—CO—O— is replaced by an -X′R′ radical for which X′ is O or S and R′ is a hydrogen atom or an alkyl or acyl radical, are also known according to Patent Application EP 74 256, cited here by way of reference.

[0005] Other camptothecin derivatives have also been disclosed, for example in the patents or patent applications, cited here by way of reference, EP 56 692, EP 88 642, EP 296 612, EP 321 122, EP 325 247, EP 540 099, EP 737 686, WO 9003169, WO 9637496, WO 9638146, WO 9638449, WO 9700876, U.S. Pat. No. 7,104,894, JP 57 116015, JP 57 116074, JP 59 005188, JP 60 019790, JP 01 249777, JP 01246287 or JP 91 012070, or in Canc. Res., 38 (1997) Abst. 1526 or 95 (San Diego, April 12-16), Canc. Res., 55(3), 603-609 (1995) or AFMC Int. Med. Chem. Symp. (1997) Abst. PB-55 (Seoul, July 27-August 1).

[0006] Irinotecan (CPT-11) and its derivatives are usually prepared from natural camptothecin (U.S. Pat. No. 4,604,463; S. Sawada et al., Chem. Pharm. Bull., 39, 2574-80 (1991), Chem. Pharm. Bull., 39, 1446-54 (1991), Chem. Pharm. Bull., 39, 3183-88 (1991) and Ann. N.Y. Acad. Sci., 803, 13-28 (1996). The stages comprise the introduction of a hydroxyl functional group at the 9-position, an alkylation at the 11-position and the introduction of a radical at the 9-position.

[0007] International Patent Application WO 96/31513 has disclosed the preparation of mappicine and camptothecin derivatives by total synthesis by firstly preparing the C-D or C-D-E ring sequence.

[0008] Tetrahedron, 53(32), 11049-60 (1997), also describes total syntheses of camptothecin derivatives in which the A-B and D-E rings are prepared beforehand or, according to another aspect, the C-D-E or A-B-C sequences.

[0009] It has now been found, and it this which forms the subject matter of the present invention, that camptothecin or camptothecin derivatives of following formula (I):

[0010] in which R₁, R₂ and R₃ each represent an identical or different group chosen from:

[0011] hydrogen,

[0012] a hydroxyl group,

[0013] a halogen atom chosen from fluorine, chlorine, bromine or iodine,

[0014] linear or branched alkoxy groups comprising 1 to 4 carbon atoms,

[0015] linear or branched alkylthio groups comprising 1 to 4 carbon atoms,

[0016] (C₁-C₄)alkylamino groups optionally substituted by one or more C₁-C₄ alkyl groups,

[0017] aralkyl groups optionally substituted by a C₁-C₄ alkyl group, said aryl groups also optionally being heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen,

[0018] arylcarbonyloxy groups, said aryl groups also optionally being mono- or polycyclic heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, can be obtained by a convergent synthesis starting from a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid with particularly advantageous results.

[0019] The preferred and commercial compounds synthesized by the process of the invention are:

[0020] camptothecin, for which R₁, R₂ and R₃ represent hydrogen,

[0021] topotecan or Hycamtin®, for which R₁ is hydrogen, R₂ represents a dimethylamino-methyl group and R₃ represents a hydroxyl group,

[0022] irinotecan or Campto®, for which R₁ represents an ethyl group, R₂ represents a piperidinopiperidinocarbonyloxy group and R₃ represents hydrogen.

[0023] The process according to the invention consists in condensing a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydro-pyrancarboxylic acid, followed by an ethynylation stage, optionally by a hydrolysis stage, by a double cyclization stage, by a dehydrogenation and by a deprotection/dealkoxycarbonylation stage.

[0024] According to the invention, 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid with the structure:

[0025] in which G₁, represents hydrogen or a protective group for the hydroxyl functional group chosen in particular from the benzyl, para-methoxybenzyl, methoxymethyl, tert-butyl and trialkylsilyl groups, at least one alkyl group in the trialkylsilyl having more than two carbon atoms, is condensed with a 3-(aminomethyl)quinoline derivative of general formula:

[0026] in which R₁, R₂ and R₃ have the same meaning as in the formula (I) or represent protected radicals or radicals which can be easily converted to R₁, R₂ and R₃ radicals mentioned above and Y represents a leaving group chosen in particular from halogen atoms or an OSO₂R radical where R represents an alkyl, tolyl, naphthyl or trifluoromethyl group, in order to obtain the quinoline derivative of general formula:

[0027] in which G₁, R₁, R₂, R₃ and Y are defined as above.

[0028] The benzyl group is preferred among the G₁ groups. Preference is given, among the Y groups, to halogens chosen from bromine or iodine and, among the OSO₂R groups, to trifluoromethylsulfonate.

[0029] The reaction is generally carried out according to the usual methods for condensing acids with amines, in particular by reaction with the acid or a reactive or activated derivative of the acid.

[0030] When the condensation of a reactive derivative of the acid of general formula (II) is carried out, the reaction is advantageously carried out by means of the acid chloride, of the anhydride, of a mixed anhydride or of a reactive ester, or of an ammonium or pyridinium acyl intermediate.

[0031] It is preferable, among the reaction conditions, to use a temperature of between −40 and +40° C. It is preferable, among the inert solvents which can be used, to use an organic solvent such as in particular a chlorinated solvent (dichloromethane, dichloroethane or chloroform, for example). The reaction can optionally be carried out in the presence of an acid acceptor, such as a nitrogenous organic base, such as, for example, pyridine, dimethyl-aminopyridine, N-methylmorpholine or a trialkylamine (in particular triethylamine or diisopropylethylamine). It is also preferable to carry out the reaction in the presence of a coupling agent, such as a carbodiimide [for example dicyclohexylcarbodiimide or 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide], N,N′-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline. The reaction is preferably carried out under argon or nitrogen.

[0032] It is understood that the amino, alkylamino or carboxyl radicals present in R₁, R₂ and R₃, like the hydroxyl functional group carried by the pyran ring, are preferably protected beforehand. Protection is carried out in particular according to the methods described by T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.), A. Wiley-Interscience Publication (1999).

[0033] Subsequently, the quinoline derivative of general formula (IV) and trialkyl (optionally substituted C₁-C₄) orthopropiolate or alkyl (optionally substituted C₁-C₄) propiolate are reacted in the presence of a palladium complex [such as, for example, tris(dibenzylideneacetone)dipalladium, bis(benzo-nitrile)palladium chloride or dichlorobis(triphenyl-phosphine)palladium] and of copper iodide and of a base, such as a tertiary amine (trialkylamine) or of an alkaline carbonate, to give the quinoline derivative of general formula:

[0034] in which R₁, R₂, R₃ and G₁ are defined as above and Alk represents a C₁-C₄ alkyl group optionally substituted by an aryl or heteroaryl group.

[0035] When the condensation is carried out in the presence of trialkyl (optionally substituted C₁-C₄) orthopropiolate, a hydrolysis stage is carried out after the condensation stage.

[0036] The condensation reaction is preferably carried out in an inert organic solvent, such as an ether (dioxane, for example), or in an amide, such as acetamide or dimethylformamide, at a temperature of between 20 and 110° C. This temperature is preferably between 20 and 80° C. and the reaction is carried out under argon or nitrogen.

[0037] The quinoline derivative of general formula (V) is subsequently cyclized by addition of a base, preferably in the presence of DBU (1,8-diazabicyclo[5.40]undec-7-ene) or of DBN (1,5-diazabicyclo[5.4.0]non-5-ene or of DABCO (1,4-diazabicyclo[2.2.2]octane, to give the tetracyclic derivative of general formula (VI):

[0038] in which Alk, R₁, R₂, R₃ and G₁ are defined as above.

[0039] As regards the reaction conditions, the reaction is preferably carried out in an anhydrous medium, in an inert organic solvent, such as an aromatic solvent (for example toluene), at a temperature of between −30 and +30° C. The reaction is preferably carried out under argon or under nitrogen.

[0040] This derivative is subsequently subjected to a cyclization to give the ester of protected camptothecin and/or of its derivatives of general formula:

[0041] in which R₁, R₂, R₃, Alk and G₁ are defined as above.

[0042] The cyclization is preferably carried out by irradiation. The irradiation is carried out alone, in the presence of an oxidizing agent, such as iodine, or with a reducing agent, such as a borohydride.

[0043] The irradiation is generally carried out in an organic solvent chosen in particular from halogenated aliphatic solvents (for example, dichloromethane or chloroform), in the first two cases mentioned above, or an alcohol (for example methanol), for the final case mentioned above, at a temperature preferably of between −30° C. and 50° C.

[0044] The derivative of formula (VII) above which does not have a double bond either on the lactone or on the piperidone and where Alk is a methyl group substituted by an aryl or heteroaryl group is subsequently hydrogenated in the presence of a palladium catalyst to give the acid, which is converted to camptothecin and/or its derivatives by the action of palladium and cymene at high temperature, optionally followed by a deprotection of the hydroxyl group on the lactone.

[0045] The derivative of formula (VII) above which has one double bond or optionally none on the piperidone can be treated with DDQ (dichlorodicyanobenzoquinone) to give the compound of formula (VII) with the two double bonds.

[0046] The derivative of general formula (VII) having two double bonds on the lactone and on the piperidone ring is finally deprotected and dealkoxycarbonylated by the action of hydrobromic acid at a temperature of between 50 and 140° C., to give camptothecin or its derivatives of general formula (I):

[0047] The 3-(aminomethyl)quinoline derivative of general formula (III) in which R₁, R₂, R₃ and Y are defined as above can be prepared by reduction of the corresponding 3-(azidomethyl)quinoline derivative of general formula:

[0048] in which R₁, R₂, R₃ and Y are defined as above.

[0049] The reduction is carried out, for example, by catalytic hydrogenation in the presence of platinum oxide in an alcoholic medium (for example, ethanol or methanol) at a temperature of between 0 and 30° C.

[0050] The 3-(azidomethyl)quinoline derivative of general formula (VIII) is prepared from the 3-methyl-quinoline derivative of general formula:

[0051] in which R₁, R₂, R₃ and Y are defined as above, the Y groups being identical or different.

[0052] The reaction is generally carried out by reaction with sodium azide in an organic solvent, such as an amide (for example dimethylformamide), at a temperature in the region of 20° C. The reaction is preferably carried out under argon or under nitrogen.

[0053] 5-Hydroxy-5-ethyl-6-oxo-5,6-dihydropyran-carboxylic acid of formula (II) is prepared from the C₁-C₄ alkyl (Alk₁) ester of 2-hydroxybutyric acid, the hydroxyl functional group of which is protected, by condensation with a compound of formula (XI) in which Alk₂ represents a C₁-C₄ alkyl group

[0054] to give the compound of following formula (XI)

[0055] in the presence of a strong base, such as an alkyllithium, LDA, alkaline hexamethyldisilazide (for example lithium hexamethyldisilazide) or alkaline tetramethylpiperidide (for example lithium tetramethylpiperidide), in an inert solvent (for example an ether, such as tetrahydrofuran).

[0056] The reaction is maintained in particular between −80 and −40° C.

[0057] The cyclization of the compound of formula (XI) is carried out in particular to the compound of following formula (XII):

[0058] in which G₁ represents a hydrogen atom or a protective group for the alcohol functional group, in the presence of a base, such as an alkaline hydroxide or an alkaline alkoxide (for example, lithium hydroxide or sodium ethoxide), in an inert solvent, such as an ether or an alcohol, at a temperature of in particular between 0 and 40° C. When the base used is an alkaline hydroxide, the saponification of the ester is carried out simultaneously; when the base used is an alkaline alkoxide, the saponification of the ester is carried out subsequently, in particular in the presence of an alkaline hydroxide. Finally, the compound is resolved according to methods known to a person skilled in the art.

[0059] The compound of formula (X) is prepared according to, for example, the protocol described by Ben Ayed, Amri and El Gaied in Tetrahedron, 1991, 47, p. 9621-9628.

[0060] The products obtained according to the process, camptothecin and its derivatives, can be purified according to the usual methods used by a person skilled in the art. For example by chromatography.

[0061] Camptothecin derivatives are usually administered by the injectable route, more particularly by the intravenous route, in the form of a sterile solution or of an emulsion. Camptothecin derivatives can also be administered by the oral route, in the form of solid or liquid compositions.

[0062] When the camptothecin derivative is administered by the intravenous route, these compositions can also comprise adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and stabilizing agents. Irinotecan (CPT-11) is in particular administered in solution in a medium for intravenous injection, at doses of between 175 to 500 mg/m².

[0063] The products of formula III, IV, V, VI, VII, VIII, XI and XII are claimed individually as novel intermediates.

[0064] The following examples, given without implying limitation, illustrate the present invention.

EXAMPLES

[0065] 2-Bromoquinolin-3-ylmethyl azide (IX)

[0066] 1.363 g (21 mmol) of NaN₃ are added, under an argon atmosphere, to a mixture of 803 mg (2.67 mmol) of dibromide and 11 ml of DMF. The mixture is stirred for 12 hours at room temperature and subsequently hydrolysed with a saturated aqueous NaCl solution.

[0067] The aqueous phase is extracted with CH₂Cl₂ and the combined organic phases are washed 3 times with water. After drying over Na₂SO₄ and evaporating under reduced pressure, chromatography on silica gel (eluent: pentane/10%-15% Et₂O) makes it possible to obtain 597 mg (2.27 mmol, 85%) of product (IX) in the form of an off-white solid.

[0068] IR (CH₂Cl₂): ν=2104 (N₃) cm⁻¹.

[0069]¹H NMR (200 MHz, CDCl₃): δ=4.60 (s, 2H, CH₂), 7.55 (ddd, 1H, aromat. H, ³J=7.9, 7.0 Hz, ⁴J=1.4 Hz), 7.68 (ddd, 1H, aromat. H, ³J=8.2, 7.0 Hz, ⁴J=1.4 Hz), 7.78 (dd, 1H, aromat. H, ³J=7.9 Hz, ⁴J=1.4 Hz), 7.99 (dd, 1H, aromat. H, ³J=8.2 Hz, ⁴J=1.4 Hz), 8.06 (s, 1H, aromat. H). ¹³C NMR (200 MHz, CDCl₃): δ=53.7 (CH₂), 127.0 (C), 127.5 (CH), 127.6 (CH), 128.3 (CH), 129.4 (C), 130.7 (CH), 136.8 (CH), 142.2 (C), 147.7 (C).

[0070] MS (EI, high resolution): Calculated: 261.9854 Found: 261.9860

[0071] Melting point: 54-56° C.

[0072] Elemental

[0073] analysis: Calculated: C 45.65%, H 2.68%, N 21.30% Found: C 45.75%, H 2.70%, N 20.96%

[0074] C-(2-Bromoquinolin-3-yl)methylamine (III)

[0075] 30 mg (0.13 mmol, 3%) of PtO₂ is added, under an argon atmosphere, to a solution of 1.015 g (3.86 mmol) of product (IX) in 110 ml of ethanol. The reaction medium is placed under a hydrogen atmosphere and stirring is maintained for 2 hours at room temperature. After filtering through celite and evaporating under reduced pressure, 863 mg (3.64 mmol, 99%) of a slightly yellow solid are obtained. The residue is used directly in the following reaction.

[0076] IR (KBr): ν=3338 (NH), 1614 (C═C), 1586, 1556 cm⁻¹

[0077]¹H NMR (200 MHz, DMSO): δ=3.92 (s, 2H, CH₂), 7.70 (m, 2H, aromat. H), 7.98 (m, 2H, aromat. H), 8.43 (s, 1H, aromat. H).

[0078]¹³C NMR (200 MHz, DMSO): δ=44.9 (CH₂), 127.3 (CH), 127.5 (CH), 127.8 (CH), 129.9 (CH), 135.9 (CH), 137.0 (C), 143.3 (C), 146.5 (C).

[0079] MS (EI, high resolution): Calculated: 235.9949 Found: 235.9954

[0080] Melting point: 131° C.

[0081] 2-(Hydroxymethyl)acrylic acid ethyl ester (XIV)

[0082] The product (XIV) is prepared according to the protocol of Villiéras and coworkers [J. Villiéras, M. Rambaud, Synthesis, 1982, 924] from 18.5 g (82.2 mmol) of triethyl phosphonoacetate, 30 ml of a 37% aqueous formaldehyde solution and 19.5 g of potassium carbonate dissolved in 20 ml of water. Purification by chromatography on silica gel (eluent: pentane/10-100% Et₂O) makes it possible to obtain 6.2 g (47.7 mmol, 58%) of the expected product. The spectroscopic data correspond to those described in the reference.

[0083] Ethyl ester of 2-(acetoxymethyl)acrylic acid (XV)

[0084] The product is prepared according to the protocol of Amri and coworkers [H. Amri, M. Rambaud and J. Villiéras, J. Org. Chem., 1990, 384, 1-11] from 2.0 g (15.4 mmol) of product (XIV), 9.3 ml of diethyl ether, 5.83 ml (6.3 g, 62 mmol) of acid anhydride and one drop of concentrated sulfuric acid. Purification by chromatography on silica gel (eluent: pentane/10% Et₂O) makes it possible to obtain 2.4 g (12.8 mmol, 83%) of product.

[0085] IR (Film): ν=1750 (C═O), 1727 (C═O), 1647 (C═C), 1233 (Ac)cm⁻¹.

[0086]¹H NMR (200 MHz, CDCl₃): δ=1.24 (t, 3H, CH₂, CH ₃, ³J=7.2 Hz), 2.04 (s, 3H, C═OCH₃), 4.18 (q, 2H, CH ₂CH₃, ³J=7.2 Hz), 4.74 (s, 2H, CH₂C═C), 5.77 (m, 1H, C═CH), 6.29 (m, 1H, C═CH).

[0087] Ethyl ester of 2-acetoxymethyl-2,3-dibromopropionic acid (XVI)

[0088] The above product is prepared according to the protocol of Amri and coworkers [T. Ben Ayed, H. Amri, M. M. El Gaied, Tetrahedron, 1991, 47, 9621-9628] from 1.0 g (5.8 mmol) of product (XV), 15 ml of tetrachloromethane and 0.31 ml (0.967 g, 6.04 mmol) of bromine. Purification by chromatography on silica gel (eluent: pentane/10% Et₂O) makes it possible to obtain 1.6 g (4.82 mmol, 83%) of the expected product. On using CH₂Cl₂ as solvent, a yield of 94% is achieved.

[0089] IR (Film): ν=2991, 2941, 2907, 2876, 1749 (C═O), 1620 (C═C), 1225 (Ac)cm⁻¹.

[0090]¹H NMR (200 MHz, CDCl₃): δ=1.32 (t, 3H, CH₂CH ₃, ³J=7.2 Hz), 2.12 (s, 3H, C═OCH₃), 3.99 (ABq, 2H, CH₂Br, δ_(a)−δ_(b)=0.176, δ_(a)=4.08, δ_(b)=3.90, ²J_(AB)=10.28 Hz), 4.31 (q, 2H, CH ₂CH₃, ³J=7.2 Hz), 4.65 (ABq, 2H, CH ₂O—COCH₃[lacuna]=0.131, δ_(a)=4.53, δ_(b)=4.40, ²J_(AB)=12.7 Hz).

[0091]¹³C NMR (200 MHz, CDCl₃): δ=14.8 (CH₃), 21.6 (CH₃), 34.0 (CH₂), 57.5 (C), 63.9 (CH₂), 65.7 (CH₂), 167.6 (C═O), 170.8 (C═O).

[0092] Ethyl ester of (E)-2-acetoxymethyl-3-bromoacrylic acid (XI)

[0093] The product (XI) is prepared according to the protocol of Amri and coworkers [T. Ben Ayed, H. Amri, M. M. El Gaied, Tetrahedron, 1991, 47, 9621-9628] from 10.0 g (30 mmol) of product of formula (XVI) obtained in the preceding stage, 13.4 g (45 mmol) of tetrabutylammonium fluoride and 20 ml of HMPA. Purification by chromatography on silica gel (eluent: pentane/10% Et₂O) makes it possible to obtain 4.14 g (16.5 mmol, 55%) of the expected product.

[0094] IR (Film): ν=1747 (C═O), 1722 (C═O), 1616 (C═C), 1227 (Ac) cm⁻¹.

[0095]¹H NMR (200 MHz CDCl₃: δ=1.25 (t, 3H, CH₂CH ₃, ³J=7.2 Hz), 2.00 (s, 3H, COCH₃), 4.19 (q, 2H, CH ₂CH₃, ³J=7.2 Hz), 4.90 (s, 2H, CH₂C═C), 7.75 (s, 1H, C═CH).

[0096] 2-Benzyloxybutyric acid

[0097] 9 ml (9.72 g, 90 mmol) of benzyl alcohol and 10.02 g (60 mmol) of α-bromobutyric acid (191) are added to a mixture of 12 g (300 mmol) of NaH in 300 ml of THF. Stirring is maintained for 30 minutes at room temperature and the suspension is subsequently brought to 50° C. for 15 hours. The mixture is poured onto ice and extracted with Et₂O. The ethereal phase is washed with a mixture of water and a small amount of solid NaHCO₃. The combined aqueous phases are acidified with aqueous HCl (5%) and extracted with Et₂O. After drying over Na₂SO₄, the solvent is evaporated under reduced pressure. 12 g of crude product are obtained, which product is used without purification in the following reaction and which product still comprises a small amount of α-bromobutyric acid.

[0098]¹H NMR (200 MHz, CDCl₃): δ=1.0 (t, 3H, CHCH₂ CH ₃ ³J=7.54 Hz), 1.87 (m, 2H, CHCH ₂CH₃), 3.95 (m, 1H, CHCH₂CH₃), 4.60 (ABq, 2H, CH ₂Ph, ²J_(AB)=11.3 Hz, δ_(a)=4.71, δ_(b)=4.49, δ_(a)−δ_(b)=0.22), 7.34 (m, 5H, aromatic H).

[0099] Methyl ester of 2-benzooxybutyric acid

[0100] The crude 2-benzyloxybutyric acid (12 g) is dissolved in Et₂O, and diazomethane in ether is subsequently added dropwise until the yellow color persists. After adding acetic acid, the solution is washed with water, dried over Na₂SO₄ and evaporated under reduced pressure. Purification by chromatography on silica gel (eluent: pentane/10% Et₂O) makes it possible to isolate 5.9 g (28.5 mmol, 48% over two stages) of the expected product. The data of the spectra correspond to those described in the reference [K. Horita, T. Inoue, K. Tanaka and O. Yonemitsu, Tetrahedron, 1996, 52, 531-550].

[0101] The product can be synthesized according to the protocol of Satoh and coworkers [H. Iwamura, Y. Imahashi, K. Kushida, K. Aoki and S. Satoh, Bull. Chem. Soc. Jpn., (1976), 49, 1690-1696].

[0102] Ethyl ester of 2-benzyloxybutyric acid

[0103]1 ml of concentrated H₂SO₄ is added, under an argon atmosphere, to a solution of 12 g of crude 2-benzyloxybutyric acid in 50 ml of dry ethanol, followed by flame-dried molecular sieve. The mixture is brought to reflux and stirring is maintained for 18 hours. The suspension is subsequently filtered through a sintered glass filter, diluted with 100 ml of ethyl acetate and washed 3 times with a saturated aqueous NaCl solution. The organic phase is dried over Na₂SO₄, evaporated under reduced pressure and purified by chromatography on silica gel (eluent: pentane/10% Et₂O). 7.5 g (33.8 mmol, 56% over 2 stages) of product are obtained.

[0104] IR (Film): ν=1746 (C═O) cm⁻¹.

[0105]¹H NMR (200 MHz, CDCl₃): δ=0.97 (t, 3H, CHCH₂CH ₃, ³J=7.2 Hz), 1.28 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 1.79 (m, 2H, CHCH ₂CH₃), 3.86 (m, 1H, CHCH₂CH₃), 4.20 (m, 2H, OCH ₂CH₃), 4.55 (ABq, 2H, PhCH ₂, ²J_(AB)=12 Hz, δ_(a)=4.70, δ_(b)=4.41, δ_(a)−δ_(b)=0.29), 7.32 (m, 5H, aromat. H).

[0106]¹³C NMR (200 MHz, CDCl₃): δ=9.6 (CH₃), 14.2 (CH₃), 26.1 (CH₂), 60.6 (CH₂), 72.1 (CH₂), 79.2 (CH), 127.7 (CH), 127.9 (CH), 128.2 (CH), 137.6 (C), 172.7 (C).

[0107] MS (DCI, NH₃+isobutane, 90 eV), m/z (%): 240 (79) [M⁺+NH₄], 223 (100) [M⁺+H].

[0108] 5-Methyl and 1-ethyl ester of (E)-2-acetoxymethyl-4-benzyloxy-4-ethylpent-2-enedioic acid (XII)

[0109] 2.16 ml (4.95 mmol, 2.3M in hexane) of n-BuLi is added at −30° C. to a solution of 0.72 ml (556 mg, 5.50 mmol) of diisopropylamine in 10 ml of THF. The temperature of the mixture is allowed to rise to 0° C. and stirring is maintained for 15 minutes. The reaction medium is subsequently cooled to −80° C. and 936 mg (4.5 mmol) of methyl ester of 2-benzyloxybutyric acid, dissolved in 4 ml of THF, are added. After 15 minutes, 1.13 g (4.5 mmol) of bromide acrylate, dissolved in 6 ml of THF, are added and stirring is maintained overnight at −80° C. The temperature is allowed to rise to −40° C. and the reaction is hydrolysed with water. After extracting with Et₂O and drying over Na₂SO₄, evaporation is carried out under reduced pressure. Purification by chromatography on silica gel (eluent: pentane/30% Et₂O) makes it possible to obtain 1.17 g (3.10 mmol, 69%) of oily product.

[0110] IR (Film): ν=1740 (C═O), 1722 (C═O), 1657 (C═C), 1236 (Ac) cm⁻¹.

[0111]¹H NMR (200 MHz, CDCl₃): δ=0.90 (CCH₂CH ₃, ³J=7.54 Hz), 1.27 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 1.83 (s, 3H, (C═O)CH ₃), 2.04 (m, 2H, CCH ₂CH₃), 3.76 (s, 3H, OCH₃), 4.22 (q, 2H, OCH ₂CH₃), ³J=7.2 Hz), 4.40 (ABq, 2H, PhCH ₂, ²J_(AB)=10.6 Hz, δ_(a)=4.42, δ_(b)=4.38, δ_(a)−δ_(b)=0.05), 5.03 (s, 2H, CH ₂O(C═O)CH₃), 7.28 (m, 6H, aromat. H+C═OC═CH).

[0112]¹³C NMR (200 MHz, CDCl₃): δ=7.9 (CH₃), 14.1 (CH₃), 20.5 (CH₃), 33.1 (CH₂), 52.6 (CH₃), 58.0 (CH₂), 61.2 (CH₂), 67.2 (CH₂), 83.6 (C), 127.1 (CH), 127.5 (CH), 127.5 (CH), 128.0 (CH), 128.3 (CH), 131.2 (C), 137.6 (C), 143.3 (CH), 165.9 (C═O), 170.2 (C═O).

[0113] MS (high resolution, FAB⁺): Calculated: 379.1757 (M⁺+H) Found: 379.1783

[0114] Diethyl ester of (E)-2-acetoxymethyl-4-benzyloxy-4-ethylpent-2-enedioic acid (XII)

[0115] 5.0 ml (11.5 mmol, 2.3M in hexane) of n-BuLi is added at −30° C. to a solution of 1.65 ml (1.27 g, 12.60 mmol) of diisopropylamine in 20 ml of THF. The temperature of the mixture is allowed to rise to 0° C. and stirring is maintained for 15 minutes. The reaction medium is subsequently cooled to −80° C. and 2.32 g (10.43 mmol) of ethyl ester of 2-benzyloxybutyric acid, dissolved in 9 ml of THF, are added. After 30 minutes, 2.62 g (10.43 mmol) of bromide acrylate, dissolved in 13 ml of THF, are added and stirring is maintained overnight at −80° C. The temperature is allowed to rise to −40° C. and the reaction is hydrolysed with water. After extracting with Et₂O and drying over Na₂SO₄, the evaporation is carried out under reduced pressure. Purification by chromatography on silica gel (eluent: pentane/20% Et₂O) makes it possible to obtain 2.33 g (5.94 mmol, 57%) of oily product.

[0116] IR (Film): ν=1738 (C═O), 1656 (C═C), 1232 (Ac) cm⁻¹.

[0117]¹H NMR (200 MHz, CDCl₃): δ=0.91 (CCH₂CH ₃, ³J=7.2 Hz), 1.29 (m, 6H, 2×OCH₂CH ₃), 1.84 (s, 3H, (C═O)CH ₃), 2.05 (m, 2H, CCH ₂CH₃), 4.24 (m, 4H, 2×OCH ₂CH₃), 4.41 (ABq, 2H, PhCH ₂, ²J_(AB)=10.96 Hz, δ_(a)=4.43, δ_(b)=4.39, δ_(a)−δ_(b)=0.04), 5.04 (s, 2H, CH ₂O(C═O)CH₃), 7.29 (m, 6H, aromat. H+C═OC═CH).

[0118]¹³C NMR (200 MHz, CDCl₃): δ=8.0 (CH₃), 14.2 (CH₃), 20.6 (CH₃), 32.2 (CH₂), 58.1 (CH₂), 61.2 (CH₂), 61.8 (CH₂), 67.2 (CH₂), 83.6 (C), 127.2 (CH), 127.5 (CH), 128.3 (CH), 131.1 (C), 143.5 (CH), 166.0 (C═O), 171.4 (C═O).

[0119] MS (high resolution, FAB⁺): Calculated: 399.1995 (M⁺+Li) Found: 399.1995

[0120] Ethyl ester of 5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyran-3-carboxylic acid (XIII)

[0121] 1.26 ml (1.26 mmol), 40 mol %, 1M in ethanol) of sodium ethoxide are added at room temperature to a solution of 1.19 g (3.16 mmol) of (E)-2-acetoxymethyl-4-benzyloxy-4-ethylpent-2-enedioic acid 1-ethyl ester 5-methyl ester dissolved in 30 ml of ethanol. Stirring is maintained for 3 hours and the mixture is hydrolysed with water. Extraction is carried out with Et₂O and the combined ethereal phases are dried over Na₂SO₄ and concentrated under reduced pressure. Chromatography on silica gel (eluent: pentane/30% Et₂O) makes it possible to obtain 737 mg (2.42 mmol, 77%) of the expected product.

[0122] IR (Film): ν=3089, 3066, 3030, 2985, 2939, 2880, 1754 (C═O), 1721 (C═O), 1675 (C═C) cm⁻¹.

[0123]¹H NMR (200 MHz, CDCl₃): δ=0.96 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.32 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 1.93 (m, 2H, CCH ₂CH₃), 4.26 (q, 2H, OCH ₂CH₃, ³J=7.2 Hz), 4.43 (ABq, 2H, PhCH ₂, ²J_(AB)=10.6 Hz, δ_(a)=4.48, δ_(b)=4.38, δ_(a)−δ_(b)=0.10), 5.09 (AB of the ABX, 2H, CH ₂C═C),δ_(a)=5.17, δ_(b)=5.01, δ_(a)−δ_(b)=0.17, ²J_(AB)=17.3 Hz, ⁴J_(AX)=1 Hz, ⁴J_(BX)=2 Hz), 6.94 (X of the ABX, 1H, (C═O)C═CH, ⁴J_(AX)=1 Hz, ⁴J_(BX)=2 Hz), 7.31 (m, 5H, aromat. H).

[0124]¹³C NMR (200 MHz, CDCl₃): δ=7.7 (CH₃), 14.0 (CH₃), 31.9 (CH₂), 61.6 (CH₂), 67.4 (CH₂), 68.5 (CH₂), 76.6 (CH₂), 127.8 (CH), 128.3 (CH), 129.5 (C), 137.4 (C), 138.8 (CH), 162.5 (C═O), 169.0 (C═O).

[0125] MS (DCI, NH₃+isobutane, 90 eV), m/z (%): 322 (100) [M⁺+NH₄], 305 (29) [M⁺+H], 214 (25) [M⁺+H−CH₂C₆H₅].

[0126] MS (FAB⁺, high resolution): Calculated: 305.1389 (M⁺+H) Found: 305.1409

[0127]5-Benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyran-3-carboxylic acid

[0128] Method A

[0129] A solution of 1.45 g (4.77 mmol) of the above product of formula (XIII) and 1.26 mg (53 mmol, 11 equiv) of lithium hydroxide in 100 ml of THF/H₂O (80/20) is stirred at room temperature overnight. The THF is removed under reduced pressure and the residue is extracted with diethyl ether. The aqueous phase is subsequently acidified to pH 4 with a 1N aqueous HCl solution. After extracting with CH₂Cl₂ (3 times), drying over Na₂SO₄ and evaporating under reduced pressure, 1.28 g (4.64 mmol, 97%) of product are obtained. It is pure enough to be used directly in the following reaction.

[0130] Method B

[0131] A solution of 800 mg (2.04 mmol) of the above product of formula (XIII) and 540 mg (22.4 mmol, 11 equiv) of lithium hydroxide in 64 ml of THF/H₂O (80/20) is stirred at room temperature overnight. The THF is removed under reduced pressure and the aqueous phase is extracted with diethyl ether. The aqueous phase is subsequently acidified to pH4 with a 1N aqueous HCl solution. After extracting with CH₂Cl₂ (3 times), drying over Na₂SO₄ and evaporating under reduced pressure, 405 mg (1.47 mmol, 72%) of product are obtained. It is pure enough to be used directly in the following reaction.

[0132] IR (Film): ν=3437 (OH), 1728 (C═O) cm⁻¹.

[0133]¹H NMR (200 MHz CDCl₃): δ=0.99 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.96 (m, 2H, CCH ₂CH₃), 4.45 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.62 Hz, δ_(a)=4.51, δ_(b)=4.39, δ_(a)−δ_(b)=0.12), 5.10 (AB of the ABX, 2H, CH ₂OC═O, ²J_(AB)=17.48 Hz, ⁴J_(AX)=1.04 Hz, ⁴J_(BX)=2.06 Hz, δ_(a)=5.18, δ_(b)=5.02, δ_(a)−δ_(b)=0.16), 7.11 (X of the ABX, 1H, (C═O)C═CH, ⁴J_(AX)=1.04 Hz), 7.31 (m, 5H, aromat. _(Phenyl) H), 10.91 (s, 1H, CO₂ H).

[0134]¹³C NMR (200 MHz, CDCl₃): δ=7.6 (CH₃), 31.8 (CH₂), 67.1 (CH₂), 68.7 (CH₂), 77.6 (C), 127.8 (CH), 127.9 (CH), 128.3 (CH), 128.7 (C), 137.1 (C), 141.6 (CH), 167.1 (C═O), 169.1 (C═O)

[0135] MS (DCI, NH₃+Isobutane, 90 eV), m/z (%): 294 (100) [M⁺+NH₃], 277 (12) [M⁺+H].

[0136] MS (FAB⁺, high resolution): Calculated: 277.1076 (M⁺+H) Found 277.1063

[0137] Elementary analysis:Calculated: C: 65.21 H: 5.84 Found: C: 65.26 H: 5.75

[0138] Melting point: 134° C.

[0139] 2-Bromoquinolin-3-ylmethyl amide of 5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyran-3-carboxylic acid (IV)

[0140] 17 mg (0.14 mmol, 9%) of DMAP are added, under an argon atmosphere, to a solution of 401 mg (1.69 mmol) of the product (III) dissolved in 4 ml of CH₂Cl₂. The mixture is cooled to 0° C. and 351 mg (1.70 mmol) of DCC are added. 426 mg (1.54 mmol) of acid obtained in the preceding stage, dissolved in 12 ml of CH₂Cl₂, are subsequently added. Stirring is maintained for 3 days at room temperature. By the end of the reaction, the mixture is diluted with Et₂O, then filtered through celite and concentrated under reduced pressure. Purification by chromatography on silica gel (eluent: CH₂Cl₂/20% Et₂O) makes it possible to obtain 714 mg (1.44 mmol, 94%) of an off-white solid.

[0141] IR (Film): ν=3351 (NH), 1748 (C═O), 1685 (NHCO), 1647 (C═C) cm⁻¹.

[0142]¹H NMR (200 MHz, CDCl₃): δ=0.90 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.88 (m, 2H, CCH₂CH₃), 4.41 (ABq, 2H, PhCH ₂, ²J_(AB)=11.32 Hz, δ_(a)=4.49, δ_(b)=4.32, δ_(a)−δ_(b)=0.17), 4.60 (d, 2H, CH₂N, ³J=5.82 Hz), 5.09 (AB of the ABX, 2H, CH₂O(C═O), ²J_(AB)=17.12 Hz, ²J_(AX)=1.04 Hz, ⁴J_(BX)=2.06 Hz, δ_(a)=5.16, δ_(b)=5.02, δ_(a)−δ_(b)=0.14), 6.41 (X of the ABX, 1H, C═CH), 6.77 (t, 1H, NH, ³J=5.48 Hz), 7.23 (m, 5H, aromat. _(Phenyl) H), 7.54 (m, 1H, aromat. _(Quino) H), 7.71 (m, 2H, aromat. _(Quino) H), 7.95 (m, 1H, aromat. _(Quino) H), 8.07 (s, 1H, aromat. _(Quino) H).

[0143]¹³C NMR (200 MHz, CDCl₃): δ=7.7 (CH₃), 31.9 (CH₂), 43.3 (CH₂), 67.8 (CH₂), 68.5 (CH₂), 76.4 (C), 127.1 (C), 127.6 (CH), 127.7 (CH), 127.8 (CH), 128.2 (CH), 128.4 (CH), 130.5 (C), 130.8 (CH), 132.1 (CH), 132.7 (C), 137.7 (C), 138.6 (CH), 139.1 (CH), 147.1 (C), 147.7 (C), 163.4 (C═O), 169.2 (C═O).

[0144] MS (eV), m/z (%): 497 (40) [M⁺+H], 495 (33) [M⁺+H] (27% of the ¹³C), 451 (12) [M⁺−CO₂], 126 (100).

[0145] Elemental analysis: C₂₅H₂₃N₂O₄Br: Calculated: C 60.62%, H 4.68%, N 5.66% Found: C 60.43%, H 4.70%, N 5.74%

[0146] 1,1,1-Triethoxy-3-trimethylsilylpropyne

TMS C(OEt)₃

[0147] 1,1,1-Triethoxy-3-trimethylsilylpropyne is obtained according to the protocol of Boche and coworkers [G. Boche, J. Bigalke, Tetrahedron. Lett., (1984), 25, 955] from 3.84 g (20 mmol) of tetraethyl orthocarbonate in 20 ml of diethyl ether, 2.84 g (20 mmol) of borotrifluoride etherate in 20 ml of diethyl ether, 1.96 g (20 mmol) of trimethylsilyl-acetylene and 8.7 ml (21 mmol) of n-butyllithium (2.4M solution in hexane) in 22 ml of diethyl ether with a yield of 74% (3.17 g, 14.8 mmol). The spectroscopic data correspond to those mentioned in the reference.

[0148] 3,3,3-Triethoxy-l-propyne

C(OEt)₃

[0149] 1.68 g of potassium carbonate are added at room temperature to a solution of 3.0 g (12.30 mmol) of 1,1,1-triethoxy-3-trimethylsilylpropyne in 180 ml of methanol. After leaving overnight, 240 ml of pentane are added and the methanol phase is separated by settling and extracted twice with pentane. The pentane phases are washed with water to pH 7. Drying over Na₂SO₄, evaporating under reduced pressure and rapid filtering through silica gel (eluent: pentane/10% Et₂O) makes it possible to obtain 1.4 g (8.14 mmol, 66%) of product.

[0150] The ¹H NMR spectrum corresponds to that provided by J. C. Shattuck (see J. C. Shattuck, A. Svato{haeck over (s)}, C. M. Blazey, J. Meinwald, Tetrahedron Lett., 38, (1997), 6803-6806).

[0151] ((2-(Triethoxyprop-1-ynyl)quinolin-3-ylmethyl)amide of 5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyran-3-carboxylic acid (V)

[0152] 260 mg (0.52 mmol) of the product of formula (IV), 15 mg (0.079 mmol, 15 mol %) of CuI and 18 mg (0.026 mmol, 5 mol %) of PdCl₂(PPh₃)₂ are dissolved under an argon atmosphere in 3.3 ml of DMF and 2.2 ml of NEt₃. After stirring for 5 minutes, 109 mg (0.64 mmol, 1.2 equiv) of 3,3,3-triethoxy-1-propyne are added. The mixture is heated in a sealed round-bottomed flask at 80° C. for 3 hours. After hydrolyzing with water and extracting with Et₂O, the combined organic phases are washed 3 times with water and once with a saturated NaCl solution. Drying is carried out over NA₂SO₄ and the solvent is subsequently removed under reduced pressure. Purification on silica gel (eluent: CH₂Cl₂/20% Et₂O) makes it possible to obtain 240 mg (0.41 mmol, 79%) of a solid.

[0153] IR (Film): ν=3372 (NH), 2235 (C≡C), 1746 (C═O), 1683 (NHCO), 1652 (C═C), 1204-1032 (orthoester) cm⁻¹.

[0154]¹H NMR (200 MHz, CDCl₃): δ=0.90 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.22 (t, 9H, 3×OCH₂CH ₃, ³J=7.2 Hz), 1.67 (m, 2H, CCH ₂CH₃), 3.77 (q, 6H, 3×OCH ₂CH₃, ³J=7.2 Hz), 4.39 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.98 Hz, δ_(a)=4.41, δ_(b)=4.37, δ_(a)−δ_(b)=0.046), 4.69 (d, 2H, CH₂N, ³J=6.16 Hz), 5.09 (AB of the ABX, 2H, CH _(2OC═O,) ²J_(AB)=17.14 Hz, ⁴J_(AX)=1.02 Hz, ⁴J_(BX)=2.06 Hz, δ_(a)=5.18, δ_(b)=5.00, δ_(a)−δ_(b)=0.18), 6.49 (X of the ABX, 1H, (C═O)C═CH), 7.22 (m, 6H, 5×aromat. _(Phenyl) H+NH), 7.53 (m, 1H, aromat. _(Quino) H), 7.72 (m, 2H, aromat. _(Quino) H), 8.04 (m, 1H, aromat. _(Quino) H), 8.17 (s, 1H, aromat. _(Quino) H).

[0155]¹³C NMR (200 MHz, CDCl₃): δ=7.7 (CH₃), 14.9 (CH₃), 31.9 (CH₂), 42.0 (CH₂), 59.5 (CH₂), 67.8 (CH₂), 68.3 (CH₂), 88.4 (C), 109.2 (C), 127.3 (C), 127.7 (C), 127.7 (C), 128.0 (CH), 128.3 (CH), 129.0 (CH), 130.4 (CH), 132.2 (CH), 132.5 (C), 132.7 (C), 136.7 (CH), 137.4 (C), 141.5 (C), 147.3 (C), 163.1 (C═O), 169.1 (C═O).

[0156] MS (high resolution, FAB⁺): Calculated: 587.2757 (M⁺+H) Found: 587.2786

[0157] Ethyl ester of [3-({[1-(5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyran-3-yl)methanoyl]amino}-methyl)quinolin-2-yl]propionic acid

[0158] One crystal of PTSA is added to a solution of 528 mg (0.90 mmol) of product (V) obtained in the preceding stage dissolved in 17 ml of ethanol and 3.5 ml of water. Stirring is maintained at room temperature for 3 hours. The mixture is subsequently diluted with water and extracted with CH₂Cl₂. After drying the combined organic phases over Na₂SO₄, the solvent is evaporated under reduced pressure. Purification by chromatography on silica gel (eluent: CH₂Cl₂/20% Et₂O) makes it possible to obtain 455 mg (0.89 mmol, 99%) of product.

[0159] IR (Film): ν=3359 (NH), 1752 (C═O), 1711 (C═O), 1687 (NHCO), 1649 (C═C) cm⁻¹.

[0160]¹H NMR (200 MHz, CDCl₃): δ=0.91 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.26 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 1.90 (m, 2H, CCH ₂CH₃), 4.17 (q, 2H, OCH ₂CH₃, ³J=7.2 Hz), 4.40 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.96 Hz, δ_(a)=4.45, δ_(b)=4.35, δ_(a)−δ_(b)=0.09), 4.72 (d, 2H, CH₂N, ³J=6.16 Hz), 5.14 (AB of the ABX, 2H, CH ₂OC═O, ²J_(AB)=17.3 Hz, ⁴J_(BX)=2.04 Hz, δ_(a)=5.22, δ_(b)=5.06, δ_(a)−δ_(b)=0.16), 6.59 (S, 1H, (C═O)C═CH), 7.22 (m, 6H, 5×aromat. _(Phenyl) H+NH), 7.56 (m, 1H, aromat. _(Quino) H), 7.71 (m, 2H, aromat. _(Quino) H), 7.98 (m, 1H, aromat. _(Quino) H), 8.19 (s, 1H, aromat. _(Quino) H).

[0161]¹³C NMR (200 MHz CDCl₃): δ=7.6 (CH₃), 13.9 (CH₃), 31.9 (CH₂), 41.3 (CH₂), 62.8 (CH₂), 67.9 (CH₂), 68.3 (CH₂), 82.7 (C), 83.1 (C), 127.6 (CH), 127.7 (CH), 128.2 (CH), 128.8 (CH), 129.0 (CH), 130.7 (CH), 132.3 (CH), 132.8 (C), 133.1 (C), 137.0 (CH), 137.6 (C), 139.9 (C), 147.3 (C═O), 153.3 (C═O), 163.5 (C═O).

[0162] MS (FAB, high resolution): Calculated: 513.2025 (M⁺+H) Found: 513.2043

[0163] Elementary analysis: C₂₈H₂₈N₂O₆:

[0164] Calculated: C 70.30%, H 5.51%, N 5.47% Found: C 70.16%, H 5.65%, N 5.28%

[0165] Melting point: 68° C.

[0166] Ethyl ester of {2-[1-(5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyran-3-yl)methanoyl]-1,2-dihydropyrrolo-[3,4-b]quinolin-3-ylidene}acetic acid (VI)

[0167] 362 mg (0.353 ml, 2.33 mmol, 0.7 eq) of DBU is added, under an argon atmosphere, to a solution of 1.703 g (3.33 mmol) of product obtained in the preceding stage in 40 ml of toluene. Stirring is maintained for 30 minutes. The mixture is subsequently hydrolysed with water and excited with CH₂Cl₂. The combined organic phases are washed with water, dried over Na₂SO₄ and evaporated under reduced pressure. Purification by chromatography on silica gel (eluent: CH₂Cl₂/10% Et₂O) makes it possible to obtain 1.42 g (2.77 mmol, 83%) of product, the A and B isomers of which are in a 1:1 mixture. The isomers, separated by chromatography:

[0168] A

[0169] IR (Film): ν=1753 (C═O), 1699 (C═O), 1644 (C═C) cm⁻¹.

[0170]¹H NMR (200 MHz, CDCl₃): δ=0.94 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.23 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 1.83 (m, 2H, CCH ₂CH₃), 4.15 (q, 2H, OCH ₂CH₃, ³J=7.2 Hz), 4.39 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.64 Hz, δ_(a)=4.46, δ_(b)=4.32, δ_(a)−δ_(b)=0.14), 5.10 (s, 2H, CH₂N), 5.31 (AB of the ABX, 2H, CH ₂OC═O, ²J_(AB)=16.12 Hz, ⁴J_(BX)=2.06 Hz, δ_(a)=5.38, δ_(b)=5.24, δ_(a)−δ_(b)=0.15), 6.19 (X of the ABX, 1H, (C═O)C═CH, ⁴J_(BX)=2.06 Hz), 6.59 (s, 1H, NC═CH), 7.29 (m, 5H, aromat. _(Phenyl) H), 7.62 (m, 1H, aromat. _(Quino) H), 7.82 (m, 2H, aromat. _(Quino) H), 8.17 (m, 1H, aromat. _(Quino) H), 8.21 (s, 1H, aromat. _(Quino) H).

[0171]¹³C NMR (300 MHz, CDCl₃): δ=8.2 (CH₃), 14.6 (CH₃), 31.5 (CH₂), 53.2 (CH₂), 61.0 (CH₂), 67.5 (CH₂), 68.8 (CH₂), 77.1 (C), 96.8 (CH), 127.8 (C), 128.0 (CH), 128.3 (CH), 128.6 (CH), 129.2 (C), 130.2 (CH), 130.8 (CH), 130.8 (CH), 131.8 (CH), 132.6 (C), 138.0 (C), 149.0 (C), 149.1 (C), 154.3 (C) 167.3 (C═O), 167.8 (C═O), 169.7 (C═O).

[0172] B

[0173] IR (Film): ν=1749 (C═O), 1714 (C═O), 1663 (C═C), 1634 (C═C) cm⁻¹.

[0174]¹H NMR (200 MHz, CDCl₃): δ=1.06 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.35 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 2.03 (m, 2H, CCH ₂CH₃), 4.44 (q, 2H, OCH ₂CH₃, ³J=7.2 Hz), 4.56 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.98 Hz, δ_(a)=4.64, δ_(b)=4.48, δ_(a)−δ_(b)=0.159), 4.97 (ABq, 2H, CH ₂OC═O, ²J_(AB)=15.4 Hz, δ_(a)=5.01, δ_(b)=4.93, δ_(a)−δ_(b)=0.083), 5.14 (s, 2H, CH₂N), 6.35 (s, 1H, (C═O)C═CH), 7.11 (s, 1H, NC═CH), 7.32 (m, 5H, aromat. _(Phenyl) H), 7.54 (m, 1H, aromat. _(Quino) H), 7.69 (m, 2H, aromat. _(Quino) H), 7.96 (m, 1H, aromat. _(Quino) H), 8.15 (s, 1H, aromat. _(Quino) H).

[0175]¹³C NMR (200 MHz, CDCl₃): δ=7.9 (CH₃), 14.2 (CH₃), 31.6 (CH₂), 52.6 (CH₂), 61.1 (CH₂), 67.9 (CH₂), 68.5 (CH₂), 76.6 (C), 105.7 (CH), 126.4 (C), 127.5 (CH), 127.6 (CH), 127.7 (CH), 127.8 (CH), 128.4 (CH), 129.7 (CH), 129.8 (CH), 130.0 (CH), 131.4 (CH), 133.8 (C), 137.6 (C), 148.2 (C), 152.0 (C), 165.1 (C═O), 167.4 (C═O), 169.0 (C═O).

[0176] MS (FAB⁺, high resolution A+B): Calculated: 513.2025 (M⁺+H) Found: 513.2006

[0177] Ethyl ester of 4-benzyloxy-4-ethyl-3,13-dioxo-3,4,12,13,-tetrahydro-1H-2-oxa-6,12a-diazadiazadibenzo[b,h]-fluorene-5-carboxylic acid

[0178] A solution of 103 mg (0.2 mmol) of the mixture of isomers of product (VI) and 26 mg (0.1 mmol) of iodine in 100 ml of CH₂Cl₂ is irradiated for 41 minutes in a reactor with a pyrex filter. The organic phase is washed with a saturated sodium thiosulfate solution and dried over Na₂SO₄. The solvent is subsequently removed under reduced pressure and the residue is purified by chromatography on silica gel (eluent: CH₂Cl₂/30% Et₂O). 30 mg (0.059 mmol, 30%) of yellowish product are obtained.

[0179] IR (Film): ν=1748 (C═O), 1725 (C═O), 1662 (C═C), 1629 (C═C) cm⁻¹.

[0180]¹H NMR (200 MHz, CDCl₃): δ=1.00 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.22 (t, 3H, OCH₂CH ₃, ³J=7.2 Hz), 2.52 (m, 2H, CCH ₂CH₃), 4.51 (m, 4H, OCH ₂CH₃+CH ₂Ph), 5.27 (s, 2H, CH ₂N), 5.46 (ABq, 2H, C═CCH ₂OC═OC, ²J_(AB)=17.46 Hz, δ_(a)=5.65, δ_(b)=5.27, δ_(a)−δ_(b)=0.39), 7.23 (m, 5H, aromat. _(Phenyl) H), 7.63 (m, 1H, aromat. _(Quino) H), 7.76 (m, 1H, aromat. _(Quino) H), 7.89 (m, 1H, aromat. _(Quino) H), 8.05 (d, 1H, aromat. _(Quino) H, ³J=7.88 Hz), 8.35 (s, 1H, aromat. _(Quino) H).

[0181]¹³ C NMR (200 MHz, CDCl₃): δ=8.4 (CH₃), 14.5 (CH₃), 33.7 (CH₂), 50.2 (CH₂), 62.8 (CH₂), 66.7 (CH₂), 68.4 (CH₂), 79.5 (C), 108.6 (C), 122.2 (C), 126.9 (CH), 127.7 (CH), 128.1 (C), 128.3 (CH), 128.4 (CH), 128.5 (C), 128.5 (CH), 128.8 (CH), 130.2 (CH), 130.5 (CH), 130.8 (CH), 131.2 (CH), 137.9 (C), 143.9 (C), 144.3 (C), 149.0 (C), 151.7 (C═O), 156.9 (C═O), 169.0 (C═O).

[0182] MS (FAB⁺, high resolution): Calculated: 511.1869 (M⁺+H) Found: 511.1862

[0183] Melting point: 92° C.

[0184] Methyl ester of [3-({[1-(5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyren-3-yl)methanoyl]amino}methyl)quinolin-2-yl]propionic acid

[0185] One crystal of PTSA is added, under an argon atmosphere, to a solution of 686 mg (1.20 mmol) of product (V) in 34 ml of methanol. Stirring is maintained for 2 hours at room temperature and the reaction medium is subsequently diluted with water. After 30 minutes, the suspension is extracted with CH₂Cl₂ and the organic phases are dried over Na₂SO₄ and evaporated under reduced pressure. Purification on silica gel (eluent: CH₂Cl₂/10% Et₂O) makes it possible to isolate 380 mg (0.76 mmol, 63%) of the expected product and 115 mg (0.23 mmol, 19%) of ethyl ester.

[0186] IR (Film): ν=3356 (NH), 1756 (C═O), 1718 (C═O), 1693 (NHCO), 1659 (C═C) cm⁻¹.

[0187]¹H NMR (300 MHz, CDCl₃): δ=0.87 (t, 3H, CCH₂CH ₃, ³J=7.41 Hz), 1.85 (m, 2H, CCH ₂CH₃), 3.67 (s, 3H, OCH₃), 4.36 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.98 Hz, δ_(a)=4.41, δ_(b)=4.30, δ_(a)−δ_(b)=0.11), 4.66 (d, 2H, CH₂N, ³J=6.03 Hz), 5.09 (AB of the ABX, 2H, CH ₂OC═O, ²J_(AB)=17.28 Hz, ⁴J_(AX)=0.78 Hz, ⁴J_(BX)=2.16 Hz, δ_(a)=5.20, δ_(b)=5.04, δ_(a)−δ_(b)=0.16), 6.51 (X of the ABX, 1H, (C═O)C═CH, ⁴J=1.41 Hz), 7.15 (m, 6H, 5×aromat. _(Phenyl) H+NH), 7.52 (m, 1H, aromat. _(Quino) H), 7.67 (m, 2H, aromat. _(Quino) H), 7.94 (m, 1H, aromat. _(Quino) H), 8.14 (s, 1H, aromat. _(Quino) H).

[0188]¹³C NMR (300 MHz, CDCl₃): δ=8.1 (CH₃), 32.4 (CH₂), 41.7 (CH₂), 53.6 (CH₃), 68.3 (CH₂), 68.8 (CH₂), 76.8 (C), 83.2 (C), 83.5 (C), 128.1 (CH), 128.1 (CH), 128.2 (C), 128.7 (CH), 129.3 (CH), 129.5 (CH), 131.2 (CH), 132.8 (CH), 133.3 (C), 133.5 (C), 137.5 (C), 137.5 (CH), 138.1 (C), 140.2 (C), 147.8 (C), 154.1 (C═O), 164.0 (C═O), 167.6 (C═O).

[0189] MS (DCI, NH₃+isobutane, 90 eV), m/z (%): 499 (100) [M⁺+H], 392 (9) [M⁺—OCH₂Ph].

[0190] Melting point: 75° C.

[0191] Methyl ester of {2-[1-(5-benzyloxy-5-ethyl-6-oxo-5,6-dihydro-2H-pyren-3-yl)methanoyl]-1,2-dihydropyrrolo-[3,4-b]quinolin-3-ylidene}acetic acid

[0192] 0.48 ml (0.53 mmol, 0.7 eq) of DBU is added, under an argon atmosphere, to a solution of 380 mg (0.76 mmol) of the compound obtained in the preceding stage in 8.2 ml of toluene. Stirring is maintained for 30 minutes. The mixture is subsequently hydrolysed with water and extracted with CH₂Cl₂. The combined organic phases are washed with water, dried over Na₂SO₄ and evaporated under reduced pressure. Purification by chromatography on silica gel (eluent: CH₂Cl₂/20% Et₂O) makes it possible to obtain 240 mg (0.48 mmol, 63%) of product in the form of two isomers A and B in a 1:1 ratio. The isomers, separated by chromatography:

[0193] A

[0194] IR (Film): ν=1755 (C═O), 1696 (C═ON), 1649 (C═C) cm³¹ ¹.

[0195]¹H NMR (200 MHz, CDCl₃): δ=0.94 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.83 (m, 2H, CCH ₂CH₃), 3.69 (s, 3H, OCH ₃), 4.39 (ABq, 2H, CH ₂Ph, ²J_(AB)=10.64 Hz, δ_(a)=4.45, δ_(b)=4.32, δ_(a)−δ_(b)=0.13), 5.07 (s, 2H, CH₂N), 5.31 (AB of the ABX, 2H, CH₂OC═O,²J_(AB)=16.1 Hz, ⁴J_(AX)=1.72 Hz, ⁴J_(BX)=1.36 Hz, δ_(a)=5.37, δ_(b)=5.23, δ_(a)−δ_(b)=0.14), 6.21 (X of the ABX, 1H, OCH₂C═CH), 6.58 (s, 1H, C═CH), 7.25 (m, 5H, aromat. _(Ph) H), 7.61 (m, 1H, aromat. _(Quino) H), 7.81 (m, 2H, aromat. _(Quino) H), 8.16 (m, 2H, aromat. _(Quino) H).

[0196] MS (DCI, NH₃+isobutane, 90 eV) m/z (%): 516 (5) [M⁺+NH₄], 499 (100) [M⁺+H], 407 (5), 392 (28), 241 (14).

[0197] B

[0198] IR (Film): ν=1754 (C═O), 1717 (C═ON), 1665 (C═C) cm⁻¹.

[0199]¹H NMR (200 MHz, CDCl₃): δ=1.06 (t, 3H, CCH₂CH ₃, ³J=7.54 Hz), 1.92 (m, 2H, CCH ₂CH₃), 3.92 (s, 3H, OCH ₃), 4.55 (ABq, 2H, CH ₂Ph, ²J_(AB)=11.3 Hz, δ_(a)=4.63, δ_(b)=4.48, δ_(a)−δ_(b)=0.145), 4.96 (AB of the ABX, 2H, CH₂OC═O, ²J_(AB)=16.1 Hz, ⁴J_(AX)=1.72 Hz, δ_(a)=5.00, δ_(b)=4.92, δ_(a)−δ_(b)=0.079), 5.13 (s, 2H, CH₂N), 6.36 (s, 1H, C═CH), 7.11 (s, 1H, C═CH), 7.31 (m, 5H, aromat. _(Ph) H), 7.49 (m, 1H, aromat. _(Quino) H), 7.66 (m, 2H, aromat. _(Quino) H), 7.93 (m, 2H, aromat. _(Quino) H).

[0200] MS (DCI, NH₃+isobutane, 90 eV) m/z (%): 499 (76) [M⁺+H], 392 (12) [M⁺−[lacuna]], 241 (100).

[0201] Camptothecin

[0202] A solution of 20 mg (0.04 mmol) of the photochemical product obtained above in 1 ml of HBr (48% aqueous solution) is heated in a sealed tube at 40° C. for 3.5 hours. The reaction solution is neutralized with a saturated NaHCO₃ solution. The aqueous phase is subsequently extracted 5 times with CH₂Cl₂ and the combined organic phases are dried over Na₂SO₄ and evaporated under reduced pressure.

[0203] Analysis by HPLC (μ Bondapak C-18, 3.9×300 mm, H₂O:acetonitrile:formic acid (50:50:0.5), Rt=3.95 min) of the reaction mixture after filtering through silica gel showed an approximate yield of camptothecin of 3%. The identity of the camptothecin, purified by chromatography on silica and by HPLC (several combined experiments), was confirmed by comparison of the mass spectrum and of the ¹H NMR spectrum with those of commercial camptothecin. 

1. Process for the preparation of camptothecin or of its derivatives of following formula (I):

in which R₁, R₂ and R₃ each represent an identical or different group chosen from: hydrogen, a hydroxyl group, a halogen atom chosen from fluorine, chlorine, bromine or iodine, linear or branched alkoxy groups comprising 1 to 4 carbon atoms, linear or branched alkylthio groups comprising 1 to 4 carbon atoms, (C₁-C₄) alkylamino groups optionally substituted by one or more C₁-C₄ alkyl groups, aralkyl groups optionally substituted by a C₁-C₄ alkyl group, said aryl groups also optionally being heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, arylcarbonyloxy groups, said aryl groups also optionally being mono- or polycyclic heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, by condensation of a 3-(aminomethyl)quinoline derivative and 5-hydroxy-5-ethyl-6-oxo-5,6-dihydro-pyrancarboxylic acid, followed by an ethynylation stage, optionally by a hydrolysis stage, by a double cyclization stage, by a dehydrogenation and by a deprotection/dealkoxycaronylation.
 2. Process according to claim 1, characterized in that the compounds of formula (I) are chosen from: camptothecin, for which R₁, R₂ and R₃ represent hydrogen, topotecan or Hycamtin®, for which R₁ is hydrogen, R₂ represents a dimethylaminomethyl group and R₃ represents a hydroxyl group, irinotecan or Campto®, for which R₁ represents an ethyl group, R₂ represents a piperidinopiperidinocarbonyloxy group and R₃ represents hydrogen.
 3. Process according to claim 1, characterized in that one of the 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid derivatives with the structure:

in which G₁ represents hydrogen or a protective group for the hydroxyl functional group, is condensed with a 3-(aminomethyl)quinoline derivative of general formula:

in which R₁, R₂ and R₃ have the same meaning as in the formula (1) or represent protected radicals or radicals which can be easily converted to R₁, R₂ and R₃ radicals mentioned above and Y represents a leaving group, in order to obtain the quinoline derivative of general formula:

in which G₁, R₁, R₂, R₃ and Y are defined as above.
 4. Process according to claim 3, characterized in that G₁ is chosen from the hydrogen, benzyl, para-methoxybenzyl, methoxymethyl, tert-butyl and trialkylsilyl groups, at least one alkyl group in the trialkylsilyl having more than two carbon atoms.
 5. Process according to claim 4, characterized in that G₁ is a benzyl group.
 6. Process according to claim 4, characterized in that Y is chosen from halogen atoms or an OSO₂R radical where R represents an alkyl, tolyl, naphthyl or trifluoromethyl group.
 7. Process according to claim 6, characterized in that Y is chosen from bromine, iodine or tyrifluoromethylsulfonate.
 8. Process according to claim 3, characterized in that the derivative of formula (II) is chosen from acid chloride, anhydrides, mixed anhydrides, reactive esters or an ammonium or pyridinium acyl intermediate.
 9. Process according to claim 3, characterized in that the reaction temperature is between −40 and +40° C.
 10. Process according to claim 3, characterized in that the solvent is chosen from organic solvents and preferably a chlorinated solvent.
 11. Process according to claim 3, characterized in that the reaction is carried out in the presence of an acid acceptor, such as a nitrogenous organic base.
 12. Process according to claim 11, characterized in that the nitrogenous organic base is chosen from pyridine, dimethylaminopyridine, N-methyl-orpholine or a trialkylamine.
 13. Process according to claim 3, characterized in that the reaction is carried out in the presence of a coupling agent chosen from carbodiimide, N,N′-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline.
 14. Process according to claim 1, characterized in that the ethynylation is carried out by reaction in the presence of a trialkyl (optionally substituted C₁-C₄) orthopropiolate or of an alkyl (optionally substituted C₁-C₄) propiolate and of a palladium complex and of copper iodide and of a base to give the quinoline derivative of general formula:

in which R₁, R₂, R₃ and G₁ are defined as above and Alk represents a C₁-C₄ alkyl group optionally substituted by an aryl or heteroaryl group.
 15. Process according to claim 14, characterized in that the palladium complex is chosen from tris(dibenzylideneacetone)dipalladium, bis(benzo-nitrile)palladium chloride or dichlorobis(triphenyl-phosphine)palladium.
 16. Process according to claim 14, characterized in that the base is chosen [lacuna] tertiary amines or alkaline carbonates.
 17. Process according to claim 14, characterized in that, when the condensation is carried out in the presence of trialkyl (optionally substituted C₁-C₄) orthopropiolate, a subsequent hydrolysis stage is carried out.
 18. Process according to claim 14, characterized in that the condensation reaction is carried out in an inert organic solvent, such as an ether, or in an amide, such as acetamide or dimethylformamide.
 19. Process according to claim 14, characterized in that the condensation reaction is carried out at a temperature of between 20 and 110° C. and preferably at a temperature of between 20 and 80° C.
 20. Process according to claim 1, characterized in that the derivative of formula (V) is cyclized by addition of a base to give the tetracyclic derivative of general formula (VI):

in which Alk, R₁, R₂, R₃ and G₁are defined as above.
 21. Process according to claim 20, characterized in that the base is chosen from DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) or DBN (1,5-diaza-bicyclo[5.4.0]non-5-ene or DABCO (1,4-diazabicyclo--[2.2.2]octane.
 22. Process according to claim 20, characterized in that the reaction is carried out in an anhydrous medium, in an inert organic solvent, such as an aromatic solvent, at a temperature of between −30 and +30° C.
 23. Process according to claim 1, characterized in that the compound of formula (VI) is subjected to a cyclization in order to give the ester of camptothecin and/or of its derivatives of general formula:

in which R₁, R₂, R₃, Alk and G₁ are defined as above.
 24. Process according to claim 23, characterized in that the cyclization is preferably carried out by irradiation.
 25. Process according to claim 24, characterized in that the irradiation is carried out alone, in the presence of an oxidizing agent, such as iodine, or with a reducing agent, such as a borohydride.
 26. Process according to claim 25, characterized in that the irradiation is carried out in an organic solvent chosen from halogenated aliphatic solvents, in the case of irradiation alone or of oxidizing irradiation, or in an alcohol, in the case of a reducing irradiation.
 27. Process according to claim 24, characterized in that the irradiation is carried out at a temperature of between −30° C. and 50° C.
 28. Process according to claim 1, characterized in that the derivative of formula (VII) above which does not have a double bond either on the lactone or on the piperidone and where Alk is a methyl group substituted by an aryl or heteroaryl group is subsequently hydrogenated in the presence of a palladium catalyst to give the acid, which is converted to camptothecin and/or its derivatives by the action of palladium and cymene at high temperature, optionally followed by a deprotection of the hydroxyl group in the lactone.
 29. Process according to claim 1, characterized in that the derivative of formula (VII) above which has one double bond or optionally none or on the piperidone can be treated with DDQ (dichlorodicyanobenzoquinone) to give the compound of formula (VII) with the two double bonds.
 30. Process according to claim 1, characterized in that the derivative of general formula (VII) having two double bonds on the lactone and on the piperidine ring is finally deprotected and dealkoxy-carbonylated by the action of hydrobromic acid to give camptothecin or its derivatives of general formula (I)


31. Process according to claim 30, characterized in that the deprotection and the dealkoxycarbonylation are carried out at a temperature of between 50 and 140° C.
 32. Process for the preparation of the 3-(aminomethyl)quinoline derivative of general formula (III) in which R₁, R₂, R₃ and Y are defined as above, characterized in that the corresponding 3-(azidomethyl)quinoline derivative of general formula:

in which R₁, R₂, R₃ and Y are defined as above, is reduced by catalytic hydrogenation in the presence of platinum oxide in an alcoholic medium.
 33. Process for the preparation of the 3-(azidomethyl)quinoline derivative of general formula (VIII) prepared by reaction with sodium azide from the methylquinoline derivative of general formula:

in which R₁, R₂, R₃ and Y are defined as above, the Y groups being equivalent or nonequivalent).
 34. Process for the preparation of 5-hydroxy-5-ethyl-6-oxo-5,6-dihydropyrancarboxylic acid of formula (II) by condensation of the C₁-C₄ alkyl (Alk₁) ester of 2-hydroxybutyric acid, the hydroxyl functional group of which is protected, with a compound of formula (X) in which Alk₂ represents a C₁-C₄ alkyl group

to give, as an intermediate, the compound of following formula (XI):

in the presence of a strong base chosen from alkyllithium, LDA, alkaline hexamethyldisilazide or alkaline tetramethylpiperidide, in an inert solvent, followed by a cyclization of the compound of formula (XI) is to the compound of following formula (XII):

in which G₁ represents a hydrogen atom or a protective group for the alcohol functional group, in the presence of a base, such as an alkaline hydroxide or an alkaline alkoxide, in an inert solvent, such as an ether or an alcohol, at a temperature of in particular between 0 and 40° C., followed by a resolution.
 35. Compounds of general formula:

in which R₁, R₂ and R₃ each represent an identical or different group chosen from: hydrogen, a hydroxyl group, a halogen atom chosen from fluorine, chlorine, bromine or iodine, linear or branched alkoxy groups comprising 1 to 4 carbon atoms, linear or branched alkylthio groups comprising 1 to 4 carbon atoms, (C₁-C₄)alkylamino groups optionally substituted by one or more C₁-C₄ alkyl groups, aralkyl groups optionally substituted by a C₁-C₄ alkyl group, said aryl groups also optionally being heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, arylcarbonyloxy groups, said aryl groups also optionally being mono- or polycyclic heterocycles comprising 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, Y is a leaving group and G₁ is as defined in claim
 34. 36. Compounds according to claim 35, in which Y is chosen from halogen atoms or an OSO₂R radical where R represents an alkyl, tolyl, naphthyl or trifluoromethyl group.
 37. Compounds of formula (V)

in which R₁, R₂, R₃ and G₁ are defined as in claim 35 and Alk represents a C₁-C₄ alkyl group optionally substituted by an aryl or heteroaryl group.
 38. Compounds of formula

in which R₁, R₂, R₃ and G₁ are defined as in claim 35 and Alk represents a C₁-C₄ alkyl group optionally substituted by an aryl or heteroaryl group.
 39. Compounds of formula (VII)

in which R₁, R₂, R₃ and G₁ are defined as in claim 35 and Alk represents a C₁-C₄ alkyl group optionally substituted by an aryl or heteroaryl group.
 40. Compounds of formula

in which R₁, R₂, R₃ and Y are defined in claims 35 and
 36. 41. Compounds of formula (XI)

in which Alk₁, and Alk₂ represent an alkyl (C₁-C₄) group and G₁ a protective group for the hydroxyl functional group.
 42. Compounds of formula (XII)

in which Alk₁ and Alk₂ represent a hydrogen atom or an alkyl (C₁-C₄) group and G₁ a hydrogen atom or a protective group for the hydroxyl functional group.
 43. Compounds of general formula (III)

in which R₁, R₂, R₃ and Y are defined as in claims 35 and
 36. 